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Repetitive oocyte donation: a committee opinion
Repetitive oocyte donation: a committee opinion Practice Committee of the American Society for Reproductive Medicine and Practice Committee of the Society for Assisted Reproductive Technology American Society for Reproductive Medicine and Society for Assisted Reproductive Technology, Birmingham, Alabama
This Committee Opinion concludes that donors be advised of the number of cycles/donations that a given oocyte donor may undergo. Although existing data cannot permit conclusive recommendations, a concern for the issues of Use your smartphone the safety and well-being of oocyte donors warrants consideration. This document replaces the to scan this QR code document of the same name, previously published in 2008 (Fertil Steril 2008; 90:S194–5). (Fertil and connect to the SterilÒ 2014;102:964–6. Ó2014 by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/asrmpraccom-repetitive-oocyte-donation/
D
onor cycles are relatively common in assisted reproductive technology (ART), and the annual number of cycles has increased over the years, comprising 15,973 cycles (approximately 10% of all ART cycles) in 2011 in the United States (1, 2). Women may choose to donate oocytes more than one time, giving rise to concerns about the optimal number of times that each woman should be permitted to donate, both to protect the health of the donor and to avoid issues of consanguinity. This discussion will address the issue of whether limits should be advised on the number of cycles/donations that a given oocyte donor may undergo. Although existing data cannot permit conclusive recommendations, concern for the safety and the well-being of oocyte donors warrants consideration. The practice of oocyte donation has potential risks to the donor, including the risks of controlled ovarian stimulation, the oocyte retrieval procedure, and anesthesia, among others. Whereas the recipient derives a clear and tangible benefit from oocyte donation,
the donor derives benefit only through a sense of altruism and/or financial compensation for her services. Therefore, the question arises as to whether to limit the number of times that a given oocyte donor might donate her gametes. Despite the absence of definitive, long-term follow-up, there is nonetheless a motivation on the part of ART practitioners to develop a consensus for a prudent approach. Unusual circumstances should be considered on an individual basis before surpassing the maximum number of donations proposed by these suggested limits.
INADVERTENT CONSANGUINITY Inadvertent consanguinity resulting from oocyte donation could occur if [1] a given donor has donated to two or more families and [2] the offspring were unaware of their specific genetic heritage. Previous documents on therapeutic donor insemination published by the American Society for Reproductive Medicine (ASRM) have advised an
Received June 19, 2014; revised and accepted June 20, 2014; published online July 23, 2014. Correspondence: Practice Committee, American Society for Reproductive Medicine, 1209 Montgomery Hwy., Birmingham, Alabama 35216 (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 4, October 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.06.035 964
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
arbitrary limit of no more than 25 pregnancies per sperm donor in a population of 800,000 to minimize the risk of consanguinity (3–5). Given that oocyte donation is a complex process and may result in cryopreserved embryos and an unpredictable number of pregnancies over a long period of time, it is reasonable to limit the number of donations rather than the number of pregnancies. The suggestions outlined here may require modification if the population using donor gametes represents an isolated subgroup or the specimens are distributed over a particularly small or wide geographic area.
HEALTH RISKS TO THE OOCYTE DONOR Controlled Ovarian Stimulation Controlled ovarian stimulation entails both known and potential risks. The risk of ovarian hyperstimulation syndrome (OHSS) is reported to be approximately 1%–2% per retrieval cycle. The incidence and severity of OHSS may in fact be lower in oocyte donors (6), in part owing to the absence of conception after stimulation. The use of final oocyte maturation with a GnRH agonist compared with the traditional use of hCG has been shown to dramatically reduce the risk of developing OHSS in VOL. 102 NO. 4 / OCTOBER 2014
Fertility and Sterility® oocyte donors in both large retrospective and smaller prospective studies (7–9).
Acute Procedural Risks There are real, albeit small (<0.5%), risks of acute complications, including pelvic infection, intraperitoneal hemorrhage, or ovarian torsion (7, 10, 11). The risks associated with the low levels of anesthesia generally employed for oocyte retrieval in a young, healthy population should be very small. However, idiosyncratic reactions to anesthetic agents and other anesthetic complications (e.g., aspiration) may occur.
Cancer While there continues to be concern that the use of controlled ovarian stimulation might increase the long-term risk of ovarian cancer (12), the preponderance of data does not demonstrate an association between the use of ovulationinducing agents and cancer, in particular, ovarian and breast cancers (13, 14). Moreover, the current understanding of the pathogenesis of ovarian cancer is rapidly evolving, calling into question traditional theories of the relationship between nulliparity and ovarian cancer (15).
Future Ovarian Reserve of the Donor It is not presently known whether repetitive follicular aspirations affect the donor's future ovarian reserve. Preliminary data indicate that repetitive and multiple cycles of oocyte donation do not decrease the donor's ovarian reserve as assessed by serum antim€ ullerian hormone levels (16).
Psychological Risks Oocyte donation may entail potential psychological risks (ambivalence, regret, etc.) that might occur around the time of the procedure or years later. In addition, despite the intended anonymity of the donors, the donors should be counseled that they may come in contact with children conceived from their gametes in the future. These issues should be addressed during appropriate pretreatment screening and counseling. While the risk of any of the adverse events discussed above is small, it is possible that the aggregate risk after a given number of procedures is additive. Therefore, based on these considerations, the Committee feels it is prudent to limit the participation of a given donor. Donors should be advised that, based on current practice, there are insufficient data to assure the lack of long-term problems beyond 6 cycles.
SUMMARY Oocyte donors are exposed to the risks of controlled ovarian stimulation, oocyte retrieval, and anesthesia. The risk of OHSS is estimated to occur in 1%–2% of donation cycles and may be further reduced by the use of GnRH agonists for triggering final oocyte maturation. The risk of serious acute complications associated with these procedures is small (<0.5%). VOL. 102 NO. 4 / OCTOBER 2014
As these are independent events, the cumulative risk of multiple procedures should be similarly low. The preponderance of data does not demonstrate a significant risk of future cancers in women undergoing stimulation and egg retrieval. While the data are limited, available evidence does not suggest that oocyte donation is associated with changes in the donor's ovarian reserve.
CONCLUSIONS Currently, there are no clearly documented long-term risks associated with oocyte donation and as such no definitive data upon which to base absolute recommendations. However, because of the possible health risks outlined in the preceding discussion, it is prudent to limit the number of stimulated cycles for a given oocyte donor to 6. Acknowledgments: This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Assisted Reproductive Technology (SART) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committees and the Board of Directors of ASRM and SART have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The Practice Committee acknowledges the special contribution of Anthony Propst, M.D., in the preparation of this document. The following members of the ASRM Practice Committee participated in the development of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document. Samantha Pfeifer, M.D., Jeffrey Goldberg, M.D., Roger Lobo, M.D., Margareta Pisarska, M.D., Eric Widra, M.D., Owen Davis, M.D., Michael Thomas, M.D., William Catherino, M.D., Ph.D., Mark Licht, M.D., Jay Sandlow, M.D., Mitchell Rosen, M.D., Michael Vernon, Ph.D., Daniel Dumesic, M.D., Clarisa Gracia, M.D., M.S.C.E., Randall Odem, M.D., Kim Thornton, M.D., Robert Rebar, M.D., Richard Reindollar, M.D., and Andrew La Barbera, Ph.D.
REFERENCES 1.
2.
Kawwass JF, Monsour M, Crawford S, Kissin DM, Session DR, Kulkami AD, et al. Trends and outcomes for donor oocyte cycles in the United States, 2000–2010. JAMA 2013;310:2426–34. Society for Assisted Reproductive Technology. Clinic Summary Report 2011. Available at: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx? ClinicPKID¼0. Last accessed July 1, 2014. 965
ASRM PAGES 3.
4.
5.
6. 7.
8.
9.
966
de Boer A, Oosterwijk JC, Rigters-Aris CA. Determination of a maximum number of artificial inseminations by donor children per sperm donor. Fertil Steril 1995;63:419–21. Curie-Cohen M. The frequency of consanguineous matings due to multiple use of donors in artificial insemination. Am J Hum Genet 1980;32: 589–600. Practice Committee of the American Society for Reproductive Medicine. Guidelines for gamete and embryo donation. Fertil Steril 1998;70(Suppl 3):1S–6S. Sauer MV, Paulson RJ, Lobo RA. Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors. Int J Gynaecol Obstet 1996;52:259–62. Bodri D, Guillen JJ, Polo A, Trullenque M, Esteve C, Coll O. Complications related to ovarian stimulation and oocyte retrieval in 2052 oocyte donor cycles. Reprod Biomed Online 2008;17:237–43. Galindo A, Bodri D, Guillen JJ, Colodron M, Vernaeve V, Coll O. Ovulation triggering with GnRH agonist vs. hCG in the same egg donor population undergoing donor oocyte cycles with GnRH antagonist: a prospective randomized cross-over trial. J Assist Reprod Genet 2009;26:251–6. Melo M, Busso CE, Bellver J, Alama P, Garrido N, Meseguer M, et al. GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study. Reprod Biomed Online 2009;19:486–92.
10.
11.
12.
13.
14. 15.
16.
Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound-directed follicle aspirations: a review of 2670 consecutive procedures. J Assist Reprod Genet 1993;10:72–7. Ludwig AK, Glawatz M, Griesinger G, Diedrich K, Ludwig M. Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of >1000 oocyte retrievals. Hum Reprod 2006; 21:3235–40. Whittemore AS, Harris R, Itnyre J. Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184–203. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346: 995–1000. Brinton LA, Sahasrabuddhe VV, Scoccia B. Fertility drugs and the risk of breast and gynecologic cancers. Semin Reprod Med 2012;30:131–45. Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011;11:719–25. Bukulmez O, Li Q, Carr BR, Leader B, Doody KM, Doody KJ. Repetitive oocyte donation does not decrease serum anti-Mullerian hormone levels. Fertil Steril 2010;94:905–12.
VOL. 102 NO. 4 / OCTOBER 2014
This Committee Opinion concludes that donors be advised of the number of cycles/donations that a given oocyte donor may undergo. Although existing data cannot permit conclusive recommendations, a concern for the issues of Use your smartphone the safety and well-being of oocyte donors warrants consideration. This document replaces the to scan this QR code document of the same name, previously published in 2008 (Fertil Steril 2008; 90:S194–5). (Fertil and connect to the SterilÒ 2014;102:964–6. Ó2014 by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/asrmpraccom-repetitive-oocyte-donation/
D
onor cycles are relatively common in assisted reproductive technology (ART), and the annual number of cycles has increased over the years, comprising 15,973 cycles (approximately 10% of all ART cycles) in 2011 in the United States (1, 2). Women may choose to donate oocytes more than one time, giving rise to concerns about the optimal number of times that each woman should be permitted to donate, both to protect the health of the donor and to avoid issues of consanguinity. This discussion will address the issue of whether limits should be advised on the number of cycles/donations that a given oocyte donor may undergo. Although existing data cannot permit conclusive recommendations, concern for the safety and the well-being of oocyte donors warrants consideration. The practice of oocyte donation has potential risks to the donor, including the risks of controlled ovarian stimulation, the oocyte retrieval procedure, and anesthesia, among others. Whereas the recipient derives a clear and tangible benefit from oocyte donation,
the donor derives benefit only through a sense of altruism and/or financial compensation for her services. Therefore, the question arises as to whether to limit the number of times that a given oocyte donor might donate her gametes. Despite the absence of definitive, long-term follow-up, there is nonetheless a motivation on the part of ART practitioners to develop a consensus for a prudent approach. Unusual circumstances should be considered on an individual basis before surpassing the maximum number of donations proposed by these suggested limits.
INADVERTENT CONSANGUINITY Inadvertent consanguinity resulting from oocyte donation could occur if [1] a given donor has donated to two or more families and [2] the offspring were unaware of their specific genetic heritage. Previous documents on therapeutic donor insemination published by the American Society for Reproductive Medicine (ASRM) have advised an
Received June 19, 2014; revised and accepted June 20, 2014; published online July 23, 2014. Correspondence: Practice Committee, American Society for Reproductive Medicine, 1209 Montgomery Hwy., Birmingham, Alabama 35216 (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 4, October 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.06.035 964
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
arbitrary limit of no more than 25 pregnancies per sperm donor in a population of 800,000 to minimize the risk of consanguinity (3–5). Given that oocyte donation is a complex process and may result in cryopreserved embryos and an unpredictable number of pregnancies over a long period of time, it is reasonable to limit the number of donations rather than the number of pregnancies. The suggestions outlined here may require modification if the population using donor gametes represents an isolated subgroup or the specimens are distributed over a particularly small or wide geographic area.
HEALTH RISKS TO THE OOCYTE DONOR Controlled Ovarian Stimulation Controlled ovarian stimulation entails both known and potential risks. The risk of ovarian hyperstimulation syndrome (OHSS) is reported to be approximately 1%–2% per retrieval cycle. The incidence and severity of OHSS may in fact be lower in oocyte donors (6), in part owing to the absence of conception after stimulation. The use of final oocyte maturation with a GnRH agonist compared with the traditional use of hCG has been shown to dramatically reduce the risk of developing OHSS in VOL. 102 NO. 4 / OCTOBER 2014
Fertility and Sterility® oocyte donors in both large retrospective and smaller prospective studies (7–9).
Acute Procedural Risks There are real, albeit small (<0.5%), risks of acute complications, including pelvic infection, intraperitoneal hemorrhage, or ovarian torsion (7, 10, 11). The risks associated with the low levels of anesthesia generally employed for oocyte retrieval in a young, healthy population should be very small. However, idiosyncratic reactions to anesthetic agents and other anesthetic complications (e.g., aspiration) may occur.
Cancer While there continues to be concern that the use of controlled ovarian stimulation might increase the long-term risk of ovarian cancer (12), the preponderance of data does not demonstrate an association between the use of ovulationinducing agents and cancer, in particular, ovarian and breast cancers (13, 14). Moreover, the current understanding of the pathogenesis of ovarian cancer is rapidly evolving, calling into question traditional theories of the relationship between nulliparity and ovarian cancer (15).
Future Ovarian Reserve of the Donor It is not presently known whether repetitive follicular aspirations affect the donor's future ovarian reserve. Preliminary data indicate that repetitive and multiple cycles of oocyte donation do not decrease the donor's ovarian reserve as assessed by serum antim€ ullerian hormone levels (16).
Psychological Risks Oocyte donation may entail potential psychological risks (ambivalence, regret, etc.) that might occur around the time of the procedure or years later. In addition, despite the intended anonymity of the donors, the donors should be counseled that they may come in contact with children conceived from their gametes in the future. These issues should be addressed during appropriate pretreatment screening and counseling. While the risk of any of the adverse events discussed above is small, it is possible that the aggregate risk after a given number of procedures is additive. Therefore, based on these considerations, the Committee feels it is prudent to limit the participation of a given donor. Donors should be advised that, based on current practice, there are insufficient data to assure the lack of long-term problems beyond 6 cycles.
SUMMARY Oocyte donors are exposed to the risks of controlled ovarian stimulation, oocyte retrieval, and anesthesia. The risk of OHSS is estimated to occur in 1%–2% of donation cycles and may be further reduced by the use of GnRH agonists for triggering final oocyte maturation. The risk of serious acute complications associated with these procedures is small (<0.5%). VOL. 102 NO. 4 / OCTOBER 2014
As these are independent events, the cumulative risk of multiple procedures should be similarly low. The preponderance of data does not demonstrate a significant risk of future cancers in women undergoing stimulation and egg retrieval. While the data are limited, available evidence does not suggest that oocyte donation is associated with changes in the donor's ovarian reserve.
CONCLUSIONS Currently, there are no clearly documented long-term risks associated with oocyte donation and as such no definitive data upon which to base absolute recommendations. However, because of the possible health risks outlined in the preceding discussion, it is prudent to limit the number of stimulated cycles for a given oocyte donor to 6. Acknowledgments: This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Assisted Reproductive Technology (SART) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committees and the Board of Directors of ASRM and SART have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The Practice Committee acknowledges the special contribution of Anthony Propst, M.D., in the preparation of this document. The following members of the ASRM Practice Committee participated in the development of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document. Samantha Pfeifer, M.D., Jeffrey Goldberg, M.D., Roger Lobo, M.D., Margareta Pisarska, M.D., Eric Widra, M.D., Owen Davis, M.D., Michael Thomas, M.D., William Catherino, M.D., Ph.D., Mark Licht, M.D., Jay Sandlow, M.D., Mitchell Rosen, M.D., Michael Vernon, Ph.D., Daniel Dumesic, M.D., Clarisa Gracia, M.D., M.S.C.E., Randall Odem, M.D., Kim Thornton, M.D., Robert Rebar, M.D., Richard Reindollar, M.D., and Andrew La Barbera, Ph.D.
REFERENCES 1.
2.
Kawwass JF, Monsour M, Crawford S, Kissin DM, Session DR, Kulkami AD, et al. Trends and outcomes for donor oocyte cycles in the United States, 2000–2010. JAMA 2013;310:2426–34. Society for Assisted Reproductive Technology. Clinic Summary Report 2011. Available at: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx? ClinicPKID¼0. Last accessed July 1, 2014. 965
ASRM PAGES 3.
4.
5.
6. 7.
8.
9.
966
de Boer A, Oosterwijk JC, Rigters-Aris CA. Determination of a maximum number of artificial inseminations by donor children per sperm donor. Fertil Steril 1995;63:419–21. Curie-Cohen M. The frequency of consanguineous matings due to multiple use of donors in artificial insemination. Am J Hum Genet 1980;32: 589–600. Practice Committee of the American Society for Reproductive Medicine. Guidelines for gamete and embryo donation. Fertil Steril 1998;70(Suppl 3):1S–6S. Sauer MV, Paulson RJ, Lobo RA. Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors. Int J Gynaecol Obstet 1996;52:259–62. Bodri D, Guillen JJ, Polo A, Trullenque M, Esteve C, Coll O. Complications related to ovarian stimulation and oocyte retrieval in 2052 oocyte donor cycles. Reprod Biomed Online 2008;17:237–43. Galindo A, Bodri D, Guillen JJ, Colodron M, Vernaeve V, Coll O. Ovulation triggering with GnRH agonist vs. hCG in the same egg donor population undergoing donor oocyte cycles with GnRH antagonist: a prospective randomized cross-over trial. J Assist Reprod Genet 2009;26:251–6. Melo M, Busso CE, Bellver J, Alama P, Garrido N, Meseguer M, et al. GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study. Reprod Biomed Online 2009;19:486–92.
10.
11.
12.
13.
14. 15.
16.
Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound-directed follicle aspirations: a review of 2670 consecutive procedures. J Assist Reprod Genet 1993;10:72–7. Ludwig AK, Glawatz M, Griesinger G, Diedrich K, Ludwig M. Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of >1000 oocyte retrievals. Hum Reprod 2006; 21:3235–40. Whittemore AS, Harris R, Itnyre J. Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184–203. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346: 995–1000. Brinton LA, Sahasrabuddhe VV, Scoccia B. Fertility drugs and the risk of breast and gynecologic cancers. Semin Reprod Med 2012;30:131–45. Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011;11:719–25. Bukulmez O, Li Q, Carr BR, Leader B, Doody KM, Doody KJ. Repetitive oocyte donation does not decrease serum anti-Mullerian hormone levels. Fertil Steril 2010;94:905–12.
VOL. 102 NO. 4 / OCTOBER 2014